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J. Biol. Chem., Vol. 281, Issue 52, 39990-40000, December 29, 2006

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EDD Mediates DNA Damage-induced Activation of CHK2^*

Michelle J. Henderson¹², Marcia A. Munoz¹, Darren N. Saunders, Jennifer L. Clancy, Amanda J. Russell, Brandi Williams, Darryl Pappin^¶, Kum Kum Khanna^||, Stephen P. Jackson, Robert L. Sutherland³, and Colin K. W. Watts

From the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, New South Wales 2010, Australia, Gurdon Institute and Department of Zoology, University of Cambridge, Cambridge, United Kingdom, ^||Queensland Institute of Medical Research, Herston, Queensland 4029, Australia, and ^¶Advanced Research and Technology Group, Applied Biosystems, Framingham, Massachusetts 01701

EDD, the human orthologue of Drosophila melanogaster "hyperplastic discs," is overexpressed or mutated in a number of common human cancers. Although EDD has been implicated in DNA damage signaling, a definitive role has yet to be demonstrated. Here we report a novel interaction between EDD and the DNA damage checkpoint kinase CHK2. EDD and CHK2 associate through a phospho-dependent interaction involving the CHK2 Forkhead-associated domain and a region of EDD spanning a number of putative Forkhead-associated domain-binding threonines. Using RNA interference, we demonstrate a critical role for EDD upstream of CHK2 in the DNA damage signaling pathway. EDD is necessary for the efficient activating phosphorylation of CHK2 in response to DNA damage following exposure to ionizing radiation or the radiomimetic, phleomycin. Cells depleted of EDD display impaired CHK2 kinase activity and an inability to respond to DNA damage. These results identify EDD as a novel mediator in DNA damage signal transduction via CHK2 and emphasize the potential importance of EDD in cancer.

Received for publication, March 24, 2006 , and in revised form, October 30, 2006.

^* This work was supported by the National Health and Medical Research Council of Australia; United States Army Medical Research and Materiel Command Breast Cancer Research Program Grants DAMD17-00-1-253, DAMD17-03-1-0410, and W81XWH-04-1-0445; the Cancer Council New South Wales; the Association for International Cancer Research; and a Cure Cancer Foundation Australia Macquarie Bank Fellowship. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² To whom correspondence may be addressed: Experimental Therapeutics Program, Children's Cancer Institute Australia, P.O. Box 81 (High St.), Randwick, NSW 2031, Australia. Tel.: 61-2-9382-8556; Fax: 61-2-9382-1850; E-mail: mhenderson{at}ccia.unsw.edu.au. ³ To whom correspondence may be addressed. Tel.: 61-2-9295-8322; Fax: 61-2-9295-8321; E-mail: r.sutherland{at}garvan.org.au.

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